Even though significant advances have occurred in the treatment of cancer, it still remains a major health concern. Cancer has been reported as the leading cause of death in the United States with one of every four Americans likely to be diagnosed with the disease1.
Included among the known chemotherapeutic drugs are carmustine, doxorubicin, methotrexate, paclitaxel, cyclophosphamide, procarbazine, and vinblastine, to name only a few. However, many chemotherapeutic drugs also produce undesirable side effects in the patient2,3.
Certain nonsteroidal anti-inflammatory drugs (NSAIDs) have been recognized to have broad anticancer activity in animal models alone and in combination with chemotherapy or radiation4.
Cyclooxygenase 2 (COX-2) inhibitors are known to have cancer chemopreventive and therapeutic benefits. Their clinical use, however, is limited by cardiovascular toxicities including myocardial infarction and stroke. These toxicities result from COX-2 inhibition in endothelial cells and the suppression of prostacyclin, which has vasodilatory activity and can inhibit platelet aggregation. Previous studies suggest that the anticancer properties of COX-2 inhibitors may not involve COX-2, but rather involves the inhibition of phosphodiesterase 5 (PDE5) and elevation of the intracellular signaling molecule, cyclic GMP to selectively induce the apoptosis (programmed cell death) of tumor cells5-7.
The present inventors have shown that the COX-2 inhibitor, celecoxib can inhibit PDE5 at concentrations that suppress tumor cell growth. Others have shown that the PDE5 inhibitory activity of celecoxib provides cardioprotective activity, which may explain why celecoxib has less cardiovascular toxicity compared with other COX-2 inhibitors, such as rofecoxib8.
Notwithstanding the advances in treatments for cancer and other diseases there still remains room for improved drugs that are effective, while at the same time exhibiting reduced adverse side effects.